scholarly journals Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Benedetta Apollonio ◽  
Nikolaos Ioannou ◽  
Despoina Papazoglou ◽  
Alan G. Ramsay
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Treatment Strategies ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Lymphocytic Leukemia ◽  
Cell Responses ◽  
Additional Layer ◽  
Different Types

Cancers, including lymphomas, develop in complex tissue environments where malignant cells actively promote the creation of a pro-tumoral niche that suppresses effective anti-tumor effector T cell responses. Research is revealing that the tumor microenvironment (TME) differs between different types of lymphoma, covering inflamed environments, as exemplified by Hodgkin lymphoma, to non-inflamed TMEs as seen in chronic lymphocytic leukemia (CLL) or diffuse-large B-cell lymphoma (DLBCL). In this review we consider how T cells and interferon-driven inflammatory signaling contribute to the regulation of anti-tumor immune responses, as well as sensitivity to anti-PD-1 immune checkpoint blockade immunotherapy. We discuss tumor intrinsic and extrinsic mechanisms critical to anti-tumor immune responses, as well as sensitivity to immunotherapies, before adding an additional layer of complexity within the TME: the immunoregulatory role of non-hematopoietic stromal cells that co-evolve with tumors. Studying the intricate interactions between the immune-stroma lymphoma TME should help to design next-generation immunotherapies and combination treatment strategies to overcome complex TME-driven immune suppression.

scholarly journals The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

2020 ◽  
Author(s):  
Anne Scheuerpflug ◽  
Fatima Ahmetlić ◽  
Vera Bauer ◽  
Tanja Riedel ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
B Cell Lymphoma ◽  
Cell Responses

Abstract Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYC-transgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses.

scholarly journals Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 915 ◽  
Author(s):  
Mulder ◽  
Wahlin ◽  
Österborg ◽  
Palma
Keyword(s):  
B Cell ◽  
Immune Cells ◽  
Clinical Results ◽  
Lymphocytic Leukemia ◽  
Inflammatory Microenvironment ◽  
Different Types ◽  
Survival And Growth ◽  
Characteristic Features ◽  
Insight Into

In lymphomas of B-cell origin, cancer cells orchestrate an inflammatory microenvironment of immune and stromal cells that sustain the tumor cell survival and growth, known as a tumor microenvironment (TME). The features of the TME differ between the different lymphoma types, ranging from extremely inflammatory, such as in Hodgkin lymphoma, to anergic, leading to immune deficiency and susceptibility to infections, such as in chronic lymphocytic leukemia. Understanding the characteristic features of the TME as well as the interactions between cancer and TME cells has given insight into the pathogenesis of most lymphomas and contributed to identify novel therapeutic targets. Here, we summarize the preclinical data that contributed to clarifying the role of the immune cells in the TME of different types of lymphomas of B-cell origin, and explain how the understanding of the biological background has led to new clinical applications. Moreover, we provide an overview of the clinical results of trials that assessed the safety and efficacy of drugs directly targeting TME immune cells in lymphoma patients.

scholarly journals Targeting the CD47-SIRPα signaling axis: current studies on B-cell lymphoma immunotherapy

2018 ◽  
Vol 46 (11) ◽  
pp. 4418-4426 ◽  
Author(s):  
Jin Zhang ◽  
Shenhe Jin ◽  
Xiaojun Guo ◽  
Wenbin Qian
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immunoglobulin Superfamily ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Cancer Initiation ◽  
Different Types ◽  
Signaling Axis ◽  
Tumor Growth And Metastasis

The function of the immune system in cancer initiation and progression has been widely examined. Notably, immunotherapy has become a promising approach for cancer treatment. CD47, a member of the immunoglobulin superfamily, plays an important role in the immune regulation of cancer by binding to SIRPα. Multiple studies have detected high CD47 expression on the surface of tumor cells, which indicates poor prognosis. Treatments that block the interaction of CD47 and SIRPα significantly suppress tumor growth and metastasis through diverse mechanisms, such as phagocytosis, antibody-dependent cellular cytotoxicity, and apoptosis. Recently, several studies have reported increased CD47 expression on different types of lymphoma cells, indicating that the CD47-SIRPα pathway can be used as a therapeutic target in lymphoma. This review focuses on the role of CD47-SIRPα in B-cell lymphoma and discusses promising therapeutic strategies targeting the CD47-SIRPα axis, which yield insights into the immunotherapy of B-cell lymphoma.

scholarly journals Role of Specific B-Cell Receptor Antigens in Lymphomagenesis

2020 ◽  
Vol 10 ◽  
Author(s):  
Lorenz Thurner ◽  
Sylvia Hartmann ◽  
Frank Neumann ◽  
Markus Hoth ◽  
Stephan Stilgenbauer ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Plasma Cell Dyscrasia ◽  
Gastric Malt Lymphoma

The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.

scholarly journals Monkeypox-Induced Immunity and Failure of Childhood Smallpox Vaccination To Provide Complete Protection

2007 ◽  
Vol 14 (10) ◽  
pp. 1318-1327 ◽  
Author(s):  
Kevin L. Karem ◽  
Mary Reynolds ◽  
Christine Hughes ◽  
Zach Braden ◽  
Pragati Nigam ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Smallpox Vaccination ◽  
Complete Protection ◽  
Recent Infection ◽  
Mild Disease ◽  
Cell Responses ◽  
B Cell Responses ◽  
Blood Specimens

ABSTRACT Following the U.S. monkeypox outbreak of 2003, blood specimens and clinical and epidemiologic data were collected from cases, defined by standard definition, and household contacts of cases to evaluate the role of preexisting (smallpox vaccine-derived) and acquired immunity in susceptibility to monkeypox disease and clinical outcomes. Orthopoxvirus-specific immunoglobulin G (IgG), IgM, CD4, CD8, and B-cell responses were measured at ∼7 to 14 weeks and 1 year postexposure. Associations between immune responses, smallpox vaccination, and epidemiologic and clinical data were assessed. Participants were categorized into four groups: (i) vaccinated cases, (ii) unvaccinated cases, (iii) vaccinated contacts, and (iv) unvaccinated contacts. Cases, regardless of vaccination status, were positive for orthopoxvirus-specific IgM, IgG, CD4, CD8, and B-cell responses. Antiorthopoxvirus immune responses consistent with infection were observed in some contacts who did not develop monkeypox. Vaccinated contacts maintained low levels of antiorthopoxvirus IgG, CD4, and B-cell responses, with most lacking IgM or CD8 responses. Preexisting immunity, assessed by high antiorthopoxvirus IgG levels and childhood smallpox vaccination, was associated (in a nonsignificant manner) with mild disease. Vaccination failed to provide complete protection against human monkeypox. Previously vaccinated monkeypox cases manifested antiorthopoxvirus IgM and changes in antiorthopoxvirus IgG, CD4, CD8, or B-cell responses as markers of recent infection. Antiorthopoxvirus IgM and CD8 responses occurred most frequently in monkeypox cases (vaccinated and unvaccinated), with IgG, CD4, and memory B-cell responses indicative of vaccine-derived immunity. Immune markers provided evidence of asymptomatic infections in some vaccinated, as well as unvaccinated, individuals.

scholarly journals Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3052
Author(s):  
A. Vera de Jonge ◽  
Tuna Mutis ◽  
Margaretha G. M. Roemer ◽  
Blanca Scheijen ◽  
Martine E. D. Chamuleau
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Cell Lymphoma ◽  
Treatment Strategies ◽  
B Cell Lymphoma ◽  
Lymphoid Malignancies ◽  
Dismal Prognosis ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Clinical Consequences

Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an important role in promoting escape from anti-tumor immune responses. This is of specific interest, since reversing tumor immune inhibition with immunotherapy has shown promising results in the treatment of both solid tumors and hematological malignancies. In this review, we outline the current understanding of impaired immune responses in B cell lymphoid malignancies with MYC overexpression, with a particular emphasis on diffuse large B cell lymphoma. We also discuss clinical consequences of MYC overexpression in the treatment of HGBL with novel immunotherapeutic agents and potential future treatment strategies.

scholarly journals Association of CXCR4 with IgM and IgD BCR Isotypes: Role in B Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1852-1852
Author(s):  
Eva Gentner ◽  
Andrea Nicola Mazzarello ◽  
Martin Becker ◽  
Antonella Nicolò ◽  
Valerio Renna ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cytoplasmic Tail ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
In Vitro Assays ◽  
B Cell Malignancies ◽  
Cxcr4 Signaling

Abstract B cell malignancies including chronic lymphocytic leukemia (CLL) and diffuse large B cell lymphoma (DLBCL) are age-associated diseases driven by clonal B cell proliferation. Signaling through B cell antigen receptor (BCRs) is dysregulated in these diseases. In addition to BCRs, chemokine receptors, such as CXCR4 and CXCR5, are used to predict clinical course. The chemokine receptor CXCR4 is expressed at different developmental stages of B cells, serving different homeostatic functions including migration. We previously reported that the cross-talk of CXCR4 and the BCR isotype IgD is supporting survival and activation of mature B cells in mice. In this process, the B cell marker and co-activator CD19 plays a pivotal role. Nevertheless, interaction of BCR with CXCR4 has not been analyzed in detail in B cell malignancies. In this study, we further elucidated the CXCR4 signaling in mouse as well as human B cell subsets including immature and mature B cells. Consistent with murine B cells, CXCR4 signaling in human B cells from healthy donors remains tightly linked to surface IgD-BCR expression, although CXCR4 is highly expressed in human IgG positive memory B cell compartment. Furthermore, proximity of CXCR4 and IgD in human mature B cells is reminiscent of that of mouse B cells. In contrast, IgD:CXCR4 proximity is skewed towards IgM:CXCR4 in CLL cells. In in vitro assays, unmutated (U)-CLL cells migrate better compared to mutated (M)-CLL. Nevertheless, our analyses reveal a frequent association of IgM:CXCR4 in M-CLL. Taking together our murine and human data, we propose that IgD:CXCR4 association is crucial for CXCR4 signaling in both CLL and healthy B cells. Apart from CXCR4, mutations within the immunoreceptor tyrosine-based activation motif (ITAM) residues of CD79a and CD79b are frequently associated with B cell malignancies including DLBCL. Knowing the potential role of BCR and its isotypes in CXCR4 induced signaling, we further analyzed the role of CD79a and CD79b. Here, we took advantage of transgenic mice, whose CD79a and CD79b cytoplasmic tails carrying ITAM motifs can be inducibly deleted. Our analysis reveals the indispensable role of the CD79b cytoplasmic tail, whose loss of function causes complete impairment of CXCR4 induced signaling in murine B cells. In contrast, loss of CD79a cytoplasmic tail partially blocks CXCR4 induced signaling, which could be rescued by CD19 co-stimulation. Extending our murine results, we established an in vitro read-out system to test the role of ITAM mutants derived from DLBCLs, as well as DLBCL-derived isotypes for analyzing their impact on CXCR4 signaling. Taking our findings together, IgD:CXCR4 association is crucial for CXCR4 signaling in CLL and healthy B cells. An increased association of IgM:CXCR4 in M-CLL compared to U-CLL suggests the necessity of IgD:CXCR4 for functional CXCR4 signaling. Furthermore, CD79b is crucial for CXCR4 induced signaling in mature B cells and loss of CD79b function abrogates CXCR4 signaling in mature B cells. Disclosures Chiorazzi: AR Pharma: Equity Ownership; Janssen, Inc: Consultancy.

scholarly journals CD8 Treg Cells Inhibit B-Cell Proliferation and Immunoglobulin Production

2020 ◽  
Vol 181 (12) ◽  
pp. 947-955 ◽  
Author(s):  
Sudhir Gupta ◽  
Houfen Su ◽  
Sudhanshu Agrawal
Keyword(s):  
Cell Proliferation ◽  
Immune Responses ◽  
B Cell ◽  
T Regulatory Cells ◽  
Treg Cells ◽  
Immunoglobulin Production ◽  
Cell Responses ◽  
Regulatory Effects ◽  
Iga Production

<b><i>Aim:</i></b> The role of CD4+ Treg in immune responses has been well established. More recently, a role of CD8+ T regulatory cells (CD8 Treg) in the regulation of immune responses in health and autoimmune diseases has been investigated. Furthermore, different investigators have used different markers to define CD8 Treg. Finally, regulatory effects of CD8 Treg have been studied against T-cell responses; however, their role in regulating B-cell proliferation and immunoglobulin production has not been evaluated. Therefore, in this study we examined the effect of two types of CD8 Treg on B-cell proliferation and immunoglobulin production. <b><i>Methods:</i></b> Purified CD8+ T cells were activated with anti-CD3/CD28 for 48 h and then sorted into two different types of CD8 Treg as defined by two different sets of markers, CD8+CD183+CD197+CD45RA− and CD8+CD183+CD25<sup>high</sup>CD278+. Purified B cells were cocultured with sorted CD8 Treg at 1:1, 1:1/2, and 1:1/4 ratios and activated with anti-CD40 and CpG. B-cell proliferation was assessed by the CFSE dye dilution assay and immunoglobulin production by the ELISA assay. <b><i>Results:</i></b> Our data show CD183+CD197+CD45RA−CD8 Treg significantly inhibited B-cell proliferation and inhibited IgM and IgG production but not IgA production at 1:1 ratio only. However, CD183+CD25<sup>high</sup>CD278+CD8 Treg inhibited significantly B-cell proliferation at 1:1 and 1:1/2 ratios and IgM, IgG, and IgA production at all ratios. <b><i>Conclusion:</i></b> CD8 Treg regulate B-cell responses, and CD183+CD25<sup>high</sup>CD278+CD8 Treg are more powerful regulators of B-cell proliferation and immunoglobulin production than CD183+CD197+CD45RA−CD8 Treg and, therefore, may be used as preferred markers for CD8 Treg.

scholarly journals Notch activation is pervasive in SMZL and uncommon in DLBCL: implications for Notch signaling in B-cell tumors

2021 ◽  
Vol 5 (1) ◽  
pp. 71-83
Author(s):  
Vignesh Shanmugam ◽  
Jeffrey W. Craig ◽  
Laura K. Hilton ◽  
Matthew H. Nguyen ◽  
Christopher K. Rushton ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Tumor Microenvironments ◽  
Notch Intracellular Domain ◽  
Marginal Zones ◽  
Notch Activation

Abstract Notch receptors participate in a signaling pathway in which ligand-induced proteolysis frees the Notch intracellular domain (NICD), allowing it to translocate to the nucleus, form a transcription complex, and induce target gene expression. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), splenic marginal zone B-cell lymphoma (SMZL), and distinct subsets of diffuse large B-cell lymphoma (DLBCL) are strongly associated with mutations in the 3′ end of NOTCH1 or NOTCH2 that disrupt a proline, glutamic acid, serine, and threonine (PEST) degron domain and stabilize NICD1 and NICD2. By contrast, mutations leading to constitutive Notch activation are rare in primary B-cell neoplasms, suggesting that Notch activation is confined to ligand-rich tumor microenvironments, or that cryptic strong gain-of-function mutations have been missed in prior analyses. To test these ideas, we used immunohistochemical stains to screen a broad range of B-cell tumors for Notch activation. Our analyses reveal that among small B-cell neoplasms, NICD2 is primarily detected in SMZL and is a common feature of both NOTCH2 wild-type and NOTCH2-mutated SMZLs, similar to prior findings with NOTCH1 in CLL/SLL. The greatest NOTCH2 activation was observed in NOTCH2-mutated SMZLs, particularly within splenic marginal zones. By contrast, little evidence of NOTCH2 activation was observed in DLBCL, even in NOTCH2-mutated tumors, suggesting that selective pressure for NOTCH2 activation is mainly confined to low-grade B-cell neoplasms, whereas DLBCLs with NOTCH1 mutations frequently showed evidence of ongoing NOTCH1 activation. These observations have important implications for the pathogenic role of Notch and its therapeutic targeting in B-cell lymphomas.

scholarly journals Antigen affinity discrimination is an intrinsic function of the B cell receptor

2010 ◽  
Vol 207 (5) ◽  
pp. 1095-1111 ◽  
Author(s):  
Wanli Liu ◽  
Tobias Meckel ◽  
Pavel Tolar ◽  
Hae Won Sohn ◽  
Susan K. Pierce
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Selective Advantage ◽  
Affinity Maturation ◽  
Cell Responses ◽  
Highly Sensitive

Antibody affinity maturation, a hallmark of adaptive immune responses, results from the selection of B cells expressing somatically hypermutated B cell receptors (BCRs) with increased affinity for antigens. Despite the central role of affinity maturation in antibody responses, the molecular mechanisms by which the increased affinity of a B cell for antigen is translated into a selective advantage for that B cell in immune responses is incompletely understood. We use high resolution live-cell imaging to provide evidence that the earliest BCR-intrinsic events that follow within seconds of BCR–antigen binding are highly sensitive to the affinity of the BCR for antigen. High affinity BCRs readily form oligomers and the resulting microclusters grow rapidly, resulting in enhanced recruitment of Syk kinase and calcium fluxes. Thus, B cells are able to read the affinity of antigen by BCR-intrinsic mechanisms during the earliest phases of BCR clustering, leading to the initiation of B cell responses.

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